Plasma copeptin, a surrogate marker for vasopressin (AVP), is an independent risk factor for diabetes mellitus. Higher AVP and copeptin have also been observed in individuals with low water intake. In this study, we tested the effect of six weeks water supplementation (1.5 L·day−1) on fasting plasma copeptin (PCop) concentration and urinary hydration parameters in habitual low‐drinkers identified by screening for high copeptin (PCop ≥ 10.7 pmol·L−1 in men and ≥ 6.1 pmol·L−1 in women) in stored plasma samples originally collected in 2013–2015 as part of the population‐based Malmö Offspring Study (MOS).From the 24% of the MOS population who had high copeptin, we enrolled thirty‐one healthy adults who in addition had a 24h urine osmolality (UOsm) > 600 mOsm·kg−1 at the baseline of the current study (i.e. 2.8±0.8 years after MOS). At baseline (Pre) and at the end of the six‐week water supplementation (Post), 24h urine collections for UOsm and urine volume (UVol), and fasting plasma samples for measurement of PCop and electrolytes (sodium, PNa) were obtained. In addition, a four‐day web‐based food and fluid record was completed Pre and Post intervention. Depending on distribution, Pre vs. Post differences were assessed with paired t‐test or Wilcoxon's paired rank test. Unless stated otherwise, data are presented as median [25th; 75th percentiles].The water intervention was effective in increasing mean (min; max) plain water intake from 427 (272; 582) to 1352 (997; 1707) g·day−1 (P < 0.0001), with no other observed changes in diet. This was supported by a reduction in UOsm (Pre: 879 [705; 996]; Post: 384 [319; 502] mOsm·kg−1; P < 0.001) and an increase in UVol (Pre: 1.06 [0.90; 1.20]; Post: 2.27 [1.52; 2.67] L·d−1; P < 0.001). The intervention slightly reduced mean (min; max) PNa from 141 (137–145) to 140 (137–144) mmol·L−1 without inducing any cases of hyponatremia. At baseline, PCop was 12.9 [7.4; 21.9] pmol·L−1 and did not differ from the population screening in MOS nearly three years earlier (PCop 11.8 [10.1; 13.8] pmol·L−1; P = 0.367). Six weeks of increased water intake resulted in a significant reduction of PCop (Post: 7.8 [4.6; 11.3] pmol·L−1; P < 0.001). Moreover, participants in the top tertile of baseline PCop (35.2 [21.0; 66.5] pmol·L−1) had a significantly greater reduction compared to the bottom two tertiles (−28.2 [−8.1; −58.6] vs. −1.6 [−0.3; −4.5] pmol·L−1; P < 0.001) but were otherwise similar in clinical characteristics.In conclusion, water supplementation in subjects with high copeptin is effective in lowering copeptin and appears as a safe and promising intervention with potential of lowering risk of diabetes mellitus.Support or Funding InformationThis study was supported by grants from the Swedish National Research Council, The Wallenberg Foundation Clinical Scholar, The Swedish Heart and Lung Foundation, The Göran Gustafsson Foundation and funding from Danone Research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.